It is known that enkephalin or endorphin as the analgesic peptide exists in the brain of mammalian animals, and particularly enkephalin is existing at a high level in the vesicles of the nervous cells at the nerve terminal in the brain, and also that enkephalinase is co-existing in the same areas as those where enkephalin is found. Besides, the possibility that enkephalin functions as neurotransmitters in the central nervous system of mammalian animals is suggested in the "Nature" Vol. 276, pages 523 to 526 (1980).
Furthermore, it has been revealed that acupuncture analgesia is mediated through release of the analgesic peptides such as enkephalins and endorphins in the brain (see: "Acta Physiologica Scandinavia" Vol. 100, 382.about.384 (1977). It is also reported that possibility that the analgesic activity of morphine is relying on that morphine plays a role to cause enkephalin to be released in the nervous system and be bound to opiate receptors (see: the "Life Science" No. 25, pages 53 to 60 (1979)).
We have taken the above facts into consideration and take it that an inhibitor against enkephalinase will show an analgesic activity as it is administered alone, and it is expected that the inhibitor against enkephalinase will be highly effective for eliminating or minimizing the pain of such patients who feel chronic pain owing to a low level of enkephalins or high activity of enkephalinase in the brain. It is also expected that an enkephalinase-inhibitor will be useful as an aid for enhancing the acupuncture analgesia and morphine analgesia (see: the "Showa Igakukai Zasshi" Vol. 39, No. 5, pages 543 to 550 (1979)).
In an attempt to provide a new analgesic compound, therefore, we have extensively researched on the inhibitory activity of various known and new compounds against enkephalinase. As a result, we have previously found that some of bestatin-related compounds and some derivatives of 3-amino-2-hydroxy-4-phenylbutanoic acid show an analgesic activity as examined in animals. Based on these findings, we proposed an analgesic agent comprising these above compounds as the active ingredient [see: Japanese Patent Application First Publication (KOKAI) No. 67516/1982 and No. 65260/1983; as well as U.S. Pat. Nos. 4,395,402 and 4,474,764.].
In a further development of our research, we have examined, for the same screening purpose, new compounds, 3-[N-(mercaptoacyl)]amino-4-arylbutanoic acid and its various derivatives as newly synthesized by us, for their inhibitory activity against enkephalinase. As a result, now, we have found that a class of the new derivatives examined exhibit an useful analgesic activity, and we have reached this invention.